C-FLIP_L is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis

Activation of the caspase cascade is a pivotal step in apoptosis and can occur via death adaptor-mediated homo-oligomerization of initiator procaspases. Here we show that c-FLIP_L, a protease-deficient caspase homolog widely regarded as an apoptosis inhibitor, is enriched in the CD95 death-inducing signaling complex (DISC) and potently promotes procaspase-8 activation through hetero-dimerization. c-FLIP_L exerts its effect through its protease-like domain, which associates efficiently with the procaspase-8 protease domain and induces the enzymatic activity of the zymogen. Ectopic expression of c-FLIP_L at physiologically relevant levels enhances procaspase-8 processing in the CD95 DISC and promotes apoptosis, while a decrease of c-FLIP_L expression results in inhibition of apoptosis. c-FLIP_L acts as an apoptosis inhibitor only at high ectopic expression levels. Thus, c-FLIP_L defines a novel type of caspase regulator, distinct from the death adaptors, that can either promote or inhibit apoptosis.